Fetal anomalies
Gene: GATA5 Amber List (moderate evidence)I don't know
OMIM gene disease association for multiple congenital heart defects both AR and AD inheritance
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AR inheritance - x2 patients with congenital heart disease
PMID 28180938 Hempel et al 2017 - x1 DCDA twin female born at 28+6 weeks after PROM. Ascites, non-immune hydrops fetalis and VSD diagnosed prenatally at 20 weeks. Postnatally diagnosed with ASD, PDA, mild HCM and gallstones. Hydrops likely secondary to congenital heart disease. Also diagnosed with clitoromegaly with transient elevation in 17-hydroxyprogrogesterone till 10 weeks of age and normal adrenal androgen levels. 46 XX confirmed on karyotype. Proband compound het for paternally inherited GATA 5 c.56G > C, p.Ser19Trp variant and maternally inherited c.605C > T, p.Arg202Gln. Carrier arents and twin sister with c.605C > T, p.Arg202Gln unaffected. Arg202Gln absent from population database, p.Ser19Trp - 241 hets in gnomad not seen in homozygous form.
Supportive zebrafish models for GATA5 LoF. Previous mouse models suggest that GATA5 plays a role during mammalian embryogenesis, including heart developmen and progesterone receptor expression.
PMID: 27066509 Kassab et al 2015
Lebanese patient cohort with high rates of consangunity. A total of 185 patients with different forms of congenital heart disease (CHD)were screened for GATA4, GATA5, GATA6 variants + 150 healthy individuals. 2 patients with homozygous GATA5 varianst identified. One patient wtih aortic stenosis, coarctation of the aorta, VSD, PDA with homozygous p.T67P variants - in silicos benign, gnomad 4975 hets and 402 homozygotes. Another patient with double outlet right ventricle / ASD / pulmonary stenosis and homozygous p.Y142H – present in gnomad 39 hets, 0 homozygotes, unaffected consanguineous carrier parents.
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Multiple studies reporting AD inheritance for bicuspid aortic valve, congenital heart disease, DCM, AF - evidence conflicting
PMID 34461831 Ma et al 2021 BMC Cardiovascular Disorders - prospective recruitment of 130 unrelated patients with bicuspid aortic valve with complex congenital heart disease being one of the exclusion criteria. 2 heterozygous GATA5 variants identified present in population database. No segregation data.
PMID: 30229885 Alonso-Montes et al 2018, European Journal of Clinical Investigations - North of Spain cohort. 122 unrelated patients with bicuspid and 154 unaffected patients had GATA4, GATA5 and GATA6 sequencing. Missense p.Arg202Gln in GATA5 identified, absent from gnomad, in-silicos probably damaging, no segregation data.
Zhang et al 2015 PMID 25543888 - DCM cohort heterozygous GATA5 c.719G>A p.G240D identified in a family. Authors report co-segregation with DCM in multiple family members with associated VSD in 2 individuals, functional analyses showed diminished transcriptional activity. In-silicos predict possibily damaging. Variant absent from gnomad but in a region of low exome coverage
Shan et al 2014 PMID 25515806 - analysis of GATA5 gene promoter in 343 patients with VSD and 348 controls. Two novel variants reported in affected individuals but also present in unaffected parents.
PMID 24796370 Bonachea et al 2014 - Cohort of 78 bicuspid aortic patients (50 with isolated BAV and 28 with associated aortic coarctation) had GATA5 sanger sequencing analysis. x2 variants identified. p.Gln3Arg variant present in 447 hets in gnomad – inherited from unaffected mother, p.Leu233Pro – present in 359 hets – apparently de novo
PMID: 23289003 Wei et al 2013 Int Journal Medical Science - cohort of 130 unrelated patients with TOF and 200 unrelated controls. GATA5 c.559C>G p.R187G variant identified in affected individual – although variant absent from gnomad alternative aa change at same position present in gnomad including truncating frameshift variants. GATA5 c.620A>G p.H207R – absent from gnomad. Authors report co-segregation of both variants with TOF in multiple family members, some with additional congenital heart defects.
Wei et al Pediatric Cardiology 2013 PMID 22961344 - GATA5 sequenced in 120 unrelated patients with VSD and 200 controls. Heterozygous GATA5 variant p.L199V identified in a patient with VSD. Author reports co-segregation in multiple affected family members. Variant absent from gnomad with X1 synonymous het variant only at same positionCreated: 17 Jan 2022, 12:35 p.m. | Last Modified: 17 Jan 2022, 12:35 p.m.
Panel Version: 0.2366
Heterozygous variants asociated with multiple types of congenital heart defects (septal defects, ToF). Autosomal recessive inheritance also reported in a patient with double outflow right ventricle in a consanguineous Lebanese family
Sources: Literature, Expert listCreated: 20 Dec 2021, 1:03 a.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Congenital heart defects, multiple types, 5 - #617912
Publications
Gene: gata5 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: GATA5 were changed from Congenital heart defects, multiple types, 5 - #617912 to Congenital heart defects, multiple types, 5 - MIM#617912
Publications for gene: GATA5 were set to 27066509; 23289003; 22961344; 23031282
Gene: gata5 has been classified as Amber List (Moderate Evidence).
gene: GATA5 was added gene: GATA5 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: GATA5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: GATA5 were set to 27066509; 23289003; 22961344; 23031282 Phenotypes for gene: GATA5 were set to Congenital heart defects, multiple types, 5 - #617912 Review for gene: GATA5 was set to GREEN
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Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
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We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
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Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.